Metabolic disorders in general and in particular, obesity and diabetes are the most common human health problems in the developed world. Its estimated that in developed countries around a third of the population is at least 20% overweight. In the United States, the percentage of obese people has increased from 25% at the end of the 1970's, to 33% at the beginning the 1990's. Obesity is one of the most important risk factors for NIDDM (noninsulin-dependent diabetes mellitus) which is the result of an imbalance between caloric intake and energy expenditure, and is highly correlated with insulin resistance and diabetes in experimental animals and humans.
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems. Body mass index (BMI), a measurement which compares weight and height, defines people as overweight (pre-obese) if their BMI is between 25 and 30 kg/m2, and obese when it is greater than 30 kg/m2. (see Haslam D W, James W P (2005), “Obesity”, Lancet 366 (9492): 1197-209; World Health Organization—Obesity pg 6 & 9, 2000). Obesity increases the likelihood of various diseases, particularly heart disease, type 2 diabetes, breathing difficulties during sleep, certain types of cancer, and osteoarthritis. Obesity is most commonly caused by a combination of excessive food energy intake, lack of physical activity, and genetic susceptibility, although a few cases are caused primarily by genes, endocrine disorders, medications or psychiatric illness. Evidence to support the view that some obese people eat little yet gain weight due to a slow metabolism is limited; on average obese people have a greater energy expenditure than their thin counterparts due to the energy required to maintain an increased body mass. (http://en.wikipedia.org/wiki/Obesity)
Dieting and physical exercise are the mainstays of treatment for obesity. Moreover, it is important to improve diet quality by reducing the consumption of energy-dense foods such as those high in fat and sugars, and by increasing the intake of dietary fiber. To supplement this, or in case of failure, anti-obesity drugs may be taken to reduce appetite or inhibit fat absorption. In severe cases, surgery is performed or an intragastric balloon is placed to reduce stomach volume and/or bowel length, leading to earlier satiation and reduced ability to absorb nutrients from food.
Obesity is a leading preventable cause of death worldwide, with increasing prevalence in adults and children, and authorities view it as one of the most serious public health problems of the 21st century (see Barness L A et. al., “Obesity: genetic, molecular, and environmental aspects”. Am. J. Med. Genet. A 143A (24): 3016-34, 2007). Obesity is stigmatized in much of the modern world (particularly in the Western world), though it was widely perceived as a symbol of wealth and fertility at other times in history, the low- and middle income people suffer from obesity.
Obesity considerably increases the risk of developing cardiovascular diseases as well. Coronary insufficiency, atheromatous disease, and cardiac insufficiency are at the forefront of the cardiovascular complication induced by obesity. It is estimated that if the entire population had an ideal weight, the risk of coronary insufficiency would decrease by 25% and the risk of cardiac insufficiency and of cerebral vascular accidents by 35%. The incidence of coronary diseases is doubled in subjects less than 50 years of age who are 30% overweight.
Diabetes is one of the major causes of premature illness and death worldwide. Developing countries are on the radar with huge population especially the low- and middle income people being suffering from the said disease. The reason being, lack of sufficient diagnosis and treatment, being made available to the patients. This is reflected from the number of deaths attributable to diabetes in 2010 which shows a 5.5% increase over the estimates for the year 2007. Although 80% of type 2 diabetes is preventable by changing diet, increasing physical activity and improving the living environment. Yet, without effective prevention and control programmes, the incidence of diabetes is likely to continue rising globally.
Currently it's estimated that 285 million people, corresponding to 6.4% of the worlds adult population, is living with diabetes. The number is expected to grow to 438 million by 2030, corresponding to 7.8% of the adult population. The largest age group currently affected by diabetes is between 40-59 years. By 2030 this “record” is expected to move to the 60-79 age groups with some 196 million cases. With an estimated 50.8 million people living with diabetes, India has the world's largest diabetes population, followed by China with 43.2 million. Unless addressed, the mortality and disease burden from diabetes and other NCDs will continue to increase. WHO projects that globally, deaths caused by these health problems will increase by 17% over the next decade, with the greatest increase in low- and middle-income countries, mainly in the African (27%) and Eastern Mediterranean (25%) regions. (see: IDF, Diabetes Atlas, 4th edition)
Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. Hyperglycemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems. It implicated in the development of kidney disease, eye diseases and nervous system problems. Diabetes causes about 5% of all deaths globally each year and is likely to increase by >50% in the next 10 years. Thus the pharmaceutical industry has been on a quest to characterize more promising molecular targets to satisfy stringent new criteria for anti-hyperglycaemic agents.
Type 1 diabetes, also known as insulin-dependent diabetes mellitus (IDDM), is caused by the autoimmune destruction of the insulin producing pancreatic beta-cells, and requires regular administration of exogenous insulin. Type 1 diabetes usually starts in childhood or young adulthood manifesting sudden symptoms of high blood sugar (hyperglycemia).
Type 2 diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM), manifests with an inability to adequately regulate blood-glucose levels. NIDDM may be characterized by a defect in insulin secretion or by insulin resistance. NIDDM is a genetically heterogeneous disease caused by various reasons such as genetic susceptibility to other environmental factors contributing to NIDDM, such as obesity, sedentary lifestyle, smoking, and certain drugs. NIDDM is a chronic disease resulting from defects in both insulin secretion and sensitivity. In NIDDM patients, the gradual loss of pancreatic β-cell function is a characteristic feature of disease progression that is associated with sustained hyperglycemia and poor outcome. Strategies for promoting normoglycemia have focused on enhancing glucose stimulated insulin secretion (GSIS) through the targeting of G protein-coupled receptors (GPCRs), such as the glucagon-like peptide1 (GLP-1) receptor, which have been shown to mediate this effect. In clinical therapy for NIDDM, metformin, α-glucosidase inhibitors, thiazolidines (TZDs), and sulfonylurea (SU) derivatives (SUs) are widely used as hypoglycaemic agents; however, the side effects of these compounds include hypoglycaemic episodes, weight-gain, gastrointestinal problems, and loss of therapy responsiveness.
Along with GLP-1 receptor as a major targets for the treatment of diabetes, GPR119 agonists have also been recognised as a major targets for the treatment of diabetes was discussed recently at the American Chemical Society 239th National Meeting (2010, San Francisco).
Further glucagon-like peptide 1 receptor agonists have shown promising therapeutic benefit over the existing therapy by way of body weight loss in type 2 diabetics, however these being injectables (Exenatide, marketed as Byetta) lack patient compliance there by limiting their usage. Other glucagon-like peptide 1 receptor agonists such as Liraglutide (Victoza), Albiglutide and Taspoglutide are also injectables.
GPR119 agonists have potential to achieve blood glucose control together with body weight loss in type 2 diabetics, similar to that of glucagon-like peptide 1 receptor agonists by way of oral route. Accordingly, oral GPR119 agonist would prove to a preferred choice of drug therapy for diabetics.
GPR119, a class-A (rhodopsin-like) G protein-coupled receptor, expressed primarily in the human pancreas and gastrointestinal tract, has attracted considerable interest as a drug target for NIDDM. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion and increased levels of the incretion hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide). (Overton H A et al. Cell Metab, 2006, 3, 167-175). In rodent models, orally available GPR119-specific agonists have been shown to attenuate blood glucose levels with a simultaneous body weight loss. (Shah U. see Curr Opin Drug Discov Devel. 2009 July; 12(4):519-32.).
In various animal models of type 2 diabetes and obesity, orally available, potent, selective, synthetic GPR119 agonists: i) lowers blood glucose without hypoglycaemia; ii) slow diabetes progression; and iii) reduce food intake and body weight.
GPR119 was first described by Fredriksson et al. (see Fredriksson R, et. al. FEBS Lett. 2003; 554:381-388) as a class 1 (rhodopsin-type) orphan G-protein-coupled receptor having no close primary sequence relative in the human genome. Independently, GPR119 has been studied and described in the literature under various synonyms including SNORF25 (see: Bonini et al., U.S. Pat. No. 6,221,660, U.S. Pat. No. 6,468,756), RUP3 (Jones et al., WO 2004/065380.), GPCR2 (Takeda et al., FEBS Lett. 2002; 520:97-101 2002), 19AJ (see Davey et. al., Expert Opin Ther Targets. 2004; 8:165-170.2004), OSGPR116 (see. U.S. Pat. No. 7,083,933) and glucose-dependent insulinotropic receptor (Chu et al., Keystone Symposium. Diabetes: Molecular Genetics, Signalling Pathways and Integrated Physiology, Keystone, Colo., USA, 14-19 Jan. 2007, abstract 117 and abstract 230).
Early signs of GPR119 as an attractive target were established by the teachings of Hilary Overton and colleagues from (OSI) Prosidion, who found that the naturally occurring lipid-signalling agent oleoylethanolamide, was capable of reducing the food intake and weight gain in rats, and can exert its effects through the G protein-coupled receptor (GPCR) GPR119. Found predominantly in the pancreas and digestive tract in humans and mice, as well as in the rodent brain, the mysterious/unknown function of GPR119 was solved.
The demonstration that GPR119 agonists stimulate the release of GLP-1 lends further credence to these agents having an effect on body weight, since GLP-1 is known to cause gastric deceleration and increase satiety, phenomena that lead to reduced caloric intake and weight loss in both animal models and human subjects (Meier et al., Eur J Pharmacol.; 440:269-279, 2002; Zander et al., 2002; Lancet.; 359:824-830. 2002 and Nielsen L L Drug Discov Today. 10, 703-710, 2005). Possibly as a result of their effects on GLP-1 secretion, selective small-molecule GPR119 agonists inhibit gastric emptying and suppress food intake upon acute dosing to rats, with no indication of drug-induced malaise or conditioned taste aversion (Fyfe et al., Diabetes. 55 Suppl 1:346-P, 2006; Diabetes; 56 Suppl 1:532-P, 2007; Overton et. al., Cell Metab. 3, 167-175, 2006). The hypophagic actions of GPR119 agonists lead to reduced weight gain, fat pad masses and plasma leptin/triglyceride levels when administered sub-chronically in rodent models of obesity (Fyfe et al., Diabetes. 55 Suppl 1:346-P, 2006; Diabetes; 56 Suppl 1:532-P, 2007; Overton et. al., Cell Metab. 3, 167-175, 2006). The testing of potent, selective agonists for food intake and body weight effects in GPR119-deficient mouse models has not been reported so far.
There are suggesting evidence about the isoforms of GPR119 been identified in a number of mammalian species, including rats, mice, hamsters, chimpanzees, rhesus monkeys, cattle and dogs. For example see. Fredriksson et al. FEBS Lett.; 554:381-388, 2003; U.S. Pat. No. 6,221,660; U.S. Pat. No. 6,468,756 and EP 1338651-A1.
GPR 119 is thus an attractive target from a clinical perspective mainly because of GPR119 agonists are capable of lowering blood glucose without hypoglycaemia; slowing of diabetes progression; and most importantly helping in reduction of food intake and body weight.
More recently Unmesh shah et. al., in Chapter-16 Vitamins & Harmones, Volume 84, pg 415-448 (2010), and Chapter-7. Annual reports in Med Chem 44 pg 149-170 (2009) have provided additional insight about GRP119
Patent literature belonging to some of these applicants include the following patents and/or patent applications: WO2011005929A1, WO2009126245A1, WO2008005576A1, WO2008005569A2, WO2007120702A2, WO2007120689A2, WO2007035355A2, WO06127595A1, WO06083491A2, WO06076455A2, WO2006 076243A1, WO05121121A2, WO05007658A2, WO05007647A1, WO04076413A2, WO2004065380; WO2010009183A1, WO2009012277A1, WO2008137436A1, WO2008 137435A1; WO2011041154A1, WO2010008739A2, WO2009014910A2, WO2009 123992A1, WO2008083238A2; WO2010103335A1, WO2010103334A1, WO2010 103333A1, WO2010004348A1, WO2010004347A1, WO2010001166A1, WO2009 050523A1, WO2009050522A1, WO2009034388A1, WO2008081208A1, WO2008081207 A1, WO2008081206A1, WO2008081205A1, WO2008081204A1, WO2007116230A1, WO2007116229A1, WO2007003964A1, WO2007003962A2, WO2007003961A2, WO2007 003960A1, WO05061489A1; WO2011061679A1, WO2011036576A1, WO2010 140092A1, WO2010128425A1, WO2010128414A1, WO2010106457A2; WO2011 062889A1, WO2011 062885A1, WO2011053688A1, WO2010114958A1, WO2010 114957A1, WO2010 075273A1, WO2010075271A1, WO2010075269A1, WO2010 009208A1, WO2010 009207A1, WO2010009195A1, WO2009143049A1, WO2009 055331A2, WO2008 130615A1, WO2008130584A1, WO2008130581A1, WO2008033465A1, WO2008 033464A2, WO2008033460A2, WO2008033456A1, WO2008033431A1, WO2011030139A1, WO2011019538A1, WO2011014520A2, WO2011008663A1, WO2011044001A1, WO2011055770A1, WO2011066137A1, WO2011078306A1, WO2011093501A1, WO2011127051A1, WO2011127106A1, WO2011128394A1, WO2011128395A1, WO2011138427A2, WO2011140160A1, WO2011140161A1, WO2011147951A1, WO2011159657A1, WO2011146335A1, WO2011145718A1, WO2011148922A1, WO2012006955A1, WO2012011707A2, WO2012025811A1, WO2012037393A1, WO2012040279A1, WO2012046249A1, WO2012045363A1, WO2012066077A1, WO2012069948A1, WO2012069917A1.
Further review and literature disclosure on GPR119 molecules have been given by Sempl, G et al., (See; Bio org. Med. Chem. Lett. (2011), doi: 10.1016/j. bmcl. 2011.03.007), Szewczyk, J. W. Et al., (See; Bio org. Med. Chem. Lett. (2011), doi:10.1016/j.bmcl. 2010.12.086), Vincent Mascitti et al., (See; Bioorganic & Medicinal Chemistry Letters 21 (2011) 1306-1309), Shigeru Yoshida et al., (See; Biochemical and Biophysical Research Communications 400 (2010) 745-751), Yulin Wu et. al., (See; Bioorganic & Medicinal Chemistry Letters 20 (2010) 2577-2581), Chu et al., (See; Endocrinology 2008 149:2038-2047), Y Ning et al., (see; British Journal of Pharmacology (2008) 155, 1056-1065), H A Overton et al., (See; British Journal of Pharmacology (2008)153, S76-S81), Carolyn Root et al., (See; Journal of Lipid Research, Volume 43, 2002, Pg 1320-1330). All of these patents and/or patent applications and literature disclosures are incorporated herein as reference in their entirety for all purposes.
Despite the advances made in the treatment of metabolic disorders and in particular in the treatment of diabetes and obesity, challenges remain in terms of the complexities of the diseases involved, and most importantly the safety concerns expected from any treatment. Accordingly, there is a need in the art for additional GPR 119 modulators with improved efficacy and safety profiles. The compounds, compositions, and pharmaceutical methods provided herein are aimed at meeting these needs.